Inflammation, Vol. 42, No. 4, August 2019 ( # 2019) DOI: 10.1007/s10753-019-00995-2

REVIEW

Targeting of IL-6-Relevant Long Noncoding RNA Profiles in Inflammatory and Tumorous Disease

Juan Zhang1 and Maolin Chu 2,3

Abstract— Interleukin-6 (IL-6) is a critical cytokine with a diverse repertoire of physio- logical functions. Dysregulation of IL-6 signaling is associated with inflammatory disorders as well as . However, blockade of IL-6 activity via antibodies directed against the IL-6 signaling pathway may compromise the efficacy of the immune system; therefore, patients may not have a uniformly satisfactory response to treatment. Long noncoding RNAs (lncRNAs) have been discovered to be evolutionary conserved transcripts of noncoding DNA sequences and have emerged as biomarkers with great predictive and prognostic value, further employed as a targeted anticancer therapy. LncRNAs have been recently implicated in the regulation of IL-6-related signaling and function; they are tightly linked to the develop- ment of a range of IL-6 dysregulated diseases. Here, we will highlight those lncRNAs involved in IL-6 signaling, with an emphasis on the mechanisms of lncRNAs that interact with IL-6. Targeting of such lncRNAs related to IL-6 regulation could be, in the near future, a promising therapeutic strategy in the treatment of inflammatory- and tumor-related diseases.

KEY WORDS: IL-6; lncRNA; inflammation; ; tumor.

INTRODUCTION growing number of publications have demonstrated that IL-6 plays a vital role in molecular disease processes, The first clinical use of chimeric antigen receptor including proliferative disorders [2], cancer stem cell for- (CAR) T cells was to treat an acute lymphoblastic leukemia mation, and maintenance in various malignant states [3]. In patient in 2017. However, this revolutionary cancer treat- light of such functionality, IL-6-blocking therapeutics ment led to a severe complication where the concentration would appear to have especially bright prospects [4]. How- of interleukin-6 (IL-6) cytokine in circulation increased to ever, concerns have been raised about the possibility of 1000 times normal levels. Fortunately, the moribund pa- increased long-term adverse events with current treatments tient made a miraculous recovery after an infusion of IL-6 targeting IL-6 [5]. For these reasons, more precise IL-6- targeting agents [1]. This anecdote underscores the impor- targeting chemotherapeutic agents will be important to tance of, IL-6, which has been risen to a new high level improve patient outcomes. because of its key role in inflammation. Similarly, a In the last few years, long noncoding RNAs (lncRNAs), classified as a novel class of transcripts greater 1 Department of Rheumatology, The First Affiliated Hospital, Harbin than 200 nucleotides, have emerged as important Medical University, 23 Youzheng St., Nan Gang District, Harbin, China expression modulators that have critical roles in the devel- 2 Department of Urology, The Second Affiliated Hospital, Harbin Medical opment of human diseases [6]. Knowledge regarding the University, 246 Xuefu St., Nan Gang District, Harbin, China mechanisms of IL-6 signaling plus the potential of 3 To whom correspondence should be addressed at Department of Urolo- gy, The Second Affiliated Hospital, Harbin Medical University, 246 targeting relevant lncRNA suggests a novel therapeutic Xuefu St., Nan Gang District, Harbin, China. E-mail: intervention [7]. It is clear exploration of the [email protected]

1139 0360-3997/19/0400-1139/0 # 2019 Springer Science+Business Media, LLC, part of Springer Nature 1140 Zhang, and Chu pathophysiological contributions and the underlying mech- MALAT1 anisms of specific lncRNAs in IL-6 dysregulated diseases Metastasis-associated lung adenocarcinoma transcript is a promising research direction. In this review, we attempt 1 (MALAT1) was originally identified as a regulator of to summarize the direct involvement of lncRNAs in vari- cancer cell survival and metastasis [10]. Recently, increas- ous parts of the IL-6 signaling pathway previously validat- ing evidence has suggested a vital regulatory effect for ed in human diseases. We also highlight the fundamental MALAT1 in IL-6 relevant inflammation. IL-6 is a hub barriers that must be overcome for IL-6-related lncRNAs to gene in the cellular response to lipopolysaccharide (LPS) enter a new era of diagnostic and therapeutic significance. treatment and induces MALAT1 upregulation in cardiomyocytes [11]. MALAT1 in turn aggravates cardiac inflammation, demonstrating increased levels of blood cy- IL-6 SIGNALING PATHWAYS IN HEALTH AND tokines including IL-6, which is achieved through the DISEASE MAPK/NFκB pathway [12]. During cerebral ischemic reperfusion injury associated with diabetes mellitus, Many inflammatory states that have a complex rela- MALAT1 in the microglia was significantly upregulated, tionship with pain, angiogenesis, as well as tumorigenesis promoting IL-6 production via MyD88 signaling [13]. and development, are characterized by excessive expres- MALAT1 has also been found to be involved in sion of IL-6. The diverse roles of IL-6 might correlate with endothelial cell functions [14]. In endothelial cells, two modes of signaling: classical and trans-signaling [8]. MALAT1 can be upregulated by IL-6 through an extracel- Next, IL-6 leads to the activation of the Janus family lular signal-regulated kinase (ERK)-dependent mechanism kinases (JAK)/signal transducer and activator of transcrip- [15], and may promote IL-6 production through activation tion (STAT3) and mitogen-activated protein kinase of amyloid antigen 3 [14]. Intervention with MALAT1 (MAPK) cascades to exert its specific actions [9]. IL-6 contributes to changes in IL-6 production by regulating expression is also regulated by nuclear factor kappa B NF-κB and p38 MAPK signaling pathways as well as (NF-κB) or STAT3. To date, IL-6 targeting monoclonal miR-146a sponging in pulmonary microvascular endothe- antibodies and JAK inhibitors have been developed to lial cells of acute lung injury [16, 17]. inhibit IL-6 signaling. However, other studies have described MALAT1 as Although IL-6 is well known for its pathological an inflammation inhibitor. Li S et al. reported that character, there are important physiological states of IL-6 MALAT1 suppressed oxidized low-density lipoprotein that should not be ignored. Firstly, anabolic side effects, (ox-LDL)-induced IL-6 release via sponging miR-155, such as increased blood lipids, are often observed during thus alleviating the inflammation persisting in atheroscle- IL-6 antagonistic therapies [8]. Furthermore, IL-6 is an rosis [18]. MALAT1 could also mitigate inflammatory important inducer of acute phase proteins even more than injury by upregulating miR-19b and inhibiting NF-κB IL-1β or alpha (TNF-α)[8]. Inhibi- pathways in murine chondrogenic ATDC5 cells [19]. Re- tion of IL-6 via the antibodies directed against IL-6/IL-6R markably MALAT1 was shown to function as a lncRNA might lead to serious long-term side effects of infection [5]. ‘decoy’ and directly interacted with NF-κβ subunits, lead- Moreover, not all patients have a positive response to IL-6 ing to attenuated NF-κβ occupancy at its target promoters blockade therefore novel drugs with more targeted preci- [20]. In the neural microvasculature of ischemic stroke, sion and efficiency should be explored. silencing of MALAT1 significantly aggravated oxygen and glucose depravation-induced expression of IL-6, sug- gesting that MALAT1 plays an anti-inflammatory role in reducing tissue damage [21]. These seemingly conflicting LNCRNAS AS PART OF THE IL-6 SIGNALING findings underscore the obscurity of lncRNA functions. PATHWAY Importantly, cell-type and tissue specificity should be con- sidered in the study of the relationship between lncRNA LncRNAs, as important transcriptional regulators af- and IL-6. fecting and thereby cell homeostasis, have demonstrated vital participation in the expression and NEAT1 signaling-regulation of IL-6. Here, we will discuss their involvement in the onset, progression, and maintenance of LncRNA nuclear-enriched abundant transcript 1 several pathologies related to IL-6 dysregulation. (NEAT1) is involved in various types of cancers. Recently, Targeting of IL-6-relevant Long Noncoding RNA Profiles 1141

NEAT1 expression was reported to be significantly upreg- LncRNAs acting on the IL-6/STAT3 pathway have ulated in patients with sepsis, and positively correlated with also been identified. In patients with sepsis, lncRNA down- serum IL-6 [22]. NEAT1 can also induce neuropathic pain regulated in liver cancer (lnc-DILC) negatively regulated development in chronic constriction injury (CCI) rats via the expression of IL-6 by modulating the signaling path- regulation of the miR-381/HMGB1 axis [23]. This mole- way STAT3/toll-like receptor 4 (TLR4) axis. LncRNA cule also participated in inflammation through sponging H19 may also regulate endothelial cell aging via inhibition miR-128 in ox-LDL-induced macrophages [24]. Remark- of STAT3 signaling [33]. LncRNA X inactivate-specific ably, downregulation of NEAT1 inhibited neuroinflamma- transcript (XIST) downregulation was shown to inhibit tion or neovascularization via inhibiting IL-6 production neuro-inflammation by reducing the expression of inflam- [23, 25]. matory cytokines through upregulating miR-544 and In autoimmune diseases, NEAT1 was reported to be downregulating STAT3 in CCI rats [34]. abnormally increased in systemic lupus erythematosus LncRNAs, novel intracellular molecular effectors of (SLE) patients and predominantly expressed in human IL-6 in cells of the innate immune system, are also in- monocytes. There was a positive correlation between volved in the molecular pathophysiology of autoimmune NEAT1 and clinical disease activity in lupus patients. diseases and may provide novel targets for therapeutic NEAT1 was further identified as activating the MAPK intervention. For example, lncRNA profiling has revealed signaling pathway with upregulation of IL-6 expression that differentially expressed lncRNAs are associated with [26]. Osteopontin (OPN), which has been reported to up- disease activity in peripheral blood mononuclear cells regulate the expression of matrix metalloprotease 13 (PBMCs) from patients with rheumatoid arthritis (RA) (MMP13) and IL-6, was significantly increased in osteo- [35]. Several other lncRNAs, such as lncRNA growth arthritis (OA). Finally, NEAT1 could rescue miR-181c arrest-specific transcript 5 (GAS5), RP11-445H22.4, and expression so as to inhibit OPN expression and lncRNA maternally expressed gene 3 (MEG3) were found synoviocyte proliferation [27]. to be closely related to osteoarthritis (OA). Moreover, MEG3 knockdown mitigated inflammatory injury via the upregulation of miR-203 in ATDC5 cells [36]. Contrast- Other lncRNAs Involved in IL-6 Dysregulated Diseases ingly, GAS5 and RP11-445H22.4 may ameliorate inflam- Inflammation Relevant Diseases. As the human body’s matory injury in cartilage ATDC5 chondrocytes by inacti- first line of defense upon injury and inflammation, IL-6 has vation of NF-κB and MAPK/ERK pathways with suppres- been implicated in the etiology of various diseases besides sion of inflammatory cytokines secretion including IL-6 infection. HOX antisense intergenic RNA (HOTAIR) is a [37, 38]. Overexpression of GAS5 aggravated IL-6 secre- lncRNA significantly induced in LPS-macrophages and tion in macrophages and mechanistic analysis showed implicated in the carcinogenic process [28]. HOTAIR GAS5 to be an endogenous sponge directly inhibiting was also obviously upregulated in ox-LDL induced mac- miR-221 expression [39]. rophages and contributed to atherosclerosis development Tumorigenesis and Metastasis. IL-6-activated STAT3 by downregulating miR-330-5 [29]. HOTAIR regulates the facilitates survival in multiple cancer cell lines and a num- activation of NF-κB and its target gene IL-6 expression by ber of lncRNAs were induced. Such a finding suggests the facilitating the degradation of IκBα [28]. Other lncRNAs existence of interplay between coding and noncoding ge- were also be found to be involved in NF-κB/IL-6 netic material [40]. Bone marrow expression of lncRNA activation. H19 was positively associated with circulating IL-6 level in In LPS-induced septic acute kidney injury, long multiple myeloma. Knockdown of H19 inhibited multiple non-coding RNA plasmacytoma variant translocation 1 myeloma cell growth via the NF-κBpathway[41]. Inter- (PVT1) was shown to increase the levels of IL-6 by estingly, lncRNAs H19 and HULC may regulate cholan- inhibiting the JNK/NF-κB signaling pathway [30]. Ins giocarcinoma cell migration and invasion by targeting IL-6 another example, lncRNA Gm4419 contributed to ox- and chemokine receptor CXCR4 through a ceRNA manner ygen glucose deprivation/reoxygenation injury in cere- [42]. LINC00460 was markedly increased and facilitates bral microglial cells via IκB phosphorylation and NF- nasopharyngeal carcinoma tumorigenesis through regulat- κB activation [31]. Suppression of lncRNA KCNQ1 ing sponging miR-149-5p/IL-6 signal pathway [43]. Su K. overlapping transcript 1 (KCNQ1OT1) may also pre- et al. have reported on a positive feedback loop between vent myocardial ischemia/reperfusion injury via p38 lncRNA upregulated in cervical cancer (lnc-UICC) and IL- MAPK/NF-κB signal pathway [32]. 6/STAT3 pathway to promote cervical cancer 1142 Zhang, and Chu

Table 1. Most Relevant lncRNAs Involved in Dysregulated IL-6 Signaling Pathway and their Target Molecules lncRNA Target Cell type or tissue Effect Disease Reference

MALAT1 miR-125b and Rat sepsis model (in vivo) Aggravate cardiac inflammation Sepsis [12] MAPK/NFκB. and dysfunction MyD88/IRAK1/ Rat microglia line HAPI Promote inflammatory response Cerebral ischemia/ [13] TRAF6 signaling. (in vitro) and cerebral I/R reperfusion (I/R) injury model in diabetic injury in diabetes rats (in vivo) mellitus Serum amyloid Human umbilical vein Upregulate inflammatory Diabetes mellitus [14] antigen 3 (SAA3) endothelial cells (in vitro) mediators IL-6 and TNF-α, and Diabetic model (in vivo) et al. for diabetes-induced vascular complications. miR-146a LPS-induced ALI rats (in vivo) Promote inflammatory response Acute lung injury [16] (ALI) NF-κB and p38 Pulmonary microvascular Promote inflammatory response Acute lung injury [17] MAPK pathways endothelial cells (PMVEC) (ALI) of rats (in vitro) and ALI rats (in vivo) miR-155 and Human coronary artery Alleviate inflammation Atherosclerosis [18] SOCS1 endothelial cells (HCAECs) stimulated with ox-LDL miR-19b and Murine chondrogenic ATDC5 Alleviated inflammatory injury Osteoarthritis [19] Wnt/β-catenin cells induced with LPS ( and NF-κB in vitro) pathways NF-κB pathways Macrophages activated with An autonegative feedback Innate immune [20] LPS (in vitro) regulator of NF-κB to help fine-tune innate immune responses Bim and E-selectin Mouse brain microvascular Inhibit inflammation to reduce Ischemic stroke [21] endothelial cells (BMECs) tissue damages (in vitro) NEAT1 miR-381/HMGB1 Chronic constriction injury Induce neuropathic pain Chronic constriction [23] axis. (CCI) rat model (in vivo) injury miR-128 RAW264.7 macrophages Participate in ox-LDL-induced Atherosclerosis [24] induced with ox-LDL inflammation and oxidative (in vivo) stress NF-κB/miR-1246 Human corneal fibroblasts Induced secretion of inflammatory Corneal neovascula- [25] pathway (HCFs) stimulated with factors to promote CRNV rization (CRNV) LPS (in vitro)andCRNV progression. rat model stimulated with LPS (in vivo) MAPK pathway Human monocytes stimulated Promote inflammation Systemic lupus [26] with LPS (in vitro) erythematosus miR-181c Human synoviocyte (in vitro) Inhibit synoviocyte proliferation Osteoarthritis [27] HOTAIR NF-κB Macrophages stimulated with Promote inflammatory and Inflammation [28] LPS (in vitro) immune response miR-330-5p Human macrophages THP-1 Promote development of Atherosclerosis [29] cells induced with ox-LDL atherosclerosis (in vitro) PVT1 Bind TNF-α and HK-2 cells induced with LPS Promote inflammatory response Septic acute kidney [30] inhibit JNK/ (in vitro) injury (AKI) NF-κBpathway KCNQ1OT1 AdipoR1 and p38 Cardiac muscle H9c2 cells Promote myocardial ischemia/ Acute [32] MAPK/NF-κB induced under condition of reperfusion myocardial pathway. oxygen glucose injury infarction deprivation(in vitro) Targeting of IL-6-relevant Long Noncoding RNA Profiles 1143

H19 STAT3 signaling Endothelial cells from Promote proliferation of Atherosclerosis [33] aged mice (in vitro) endothelial cells MEG3 miR-203 ATDC5 cells induced Promote inflammatory injury Osteoarthritis [36] with LPS (in vitro) GAS5 NF-κB and Notch ATDC5 chondrocytes Ameliorate LPS-induced Osteoarthritis [37] pathways stimulated by LPS inflammatory injury (in vitro) miR-221 THP-1 macrophage Trigger inflammatory response Atherosclerosis [39] stimulated with ox-LDL (in vitro) and atherosclerotic rat model (in vivo) RP11- miR-301a/CXCR4/ ATDC5 chondrocytes stimulated Ameliorate inflammatory injury Osteoarthritis [38] 445H22.4 NF-κBand by LPS (in vitro) MAPK/ERK pathways LINC00460 miR-149-5p/IL-6 NPC cells (in vitro) and tumor Promote NPC progression Nasopharyngeal [43] signal pathway xenografts established by carcinoma CNE-1/SUNE-1 cells (NPC) (in vivo) UICC IL-6/STAT3 Caski, SiHa, HeLa, Ms751 and Promote tumorigenesis and Cervical cancer [44] signaling C33a cells (in vitro)and metastasis in cervical tumor xenografts established cancer by HeLa cells overexpressing UICC (in vivo) BM JAK2 kinase cells (in vitro) Promote breast cancer Breast cancer [45] and murine models (in vivo) brain metastases TSLNC8 Transketolase/ HCC cells (in vitro)andtumor Suppresses proliferation Hepatocellular [46] STAT3 xenografts (in vivo) and metastasis of carcinoma (HCC) axis HCC cells CUDR NF-κB signaling Human embryonic stem Aggravate hepatocyte-like Hepatocellular [47] cells-derived hepatocyte-like stem cells malignant carcinoma stem cells (in vitro) transformation DILC IL-6/STAT3 Liver cancer stem cells (LCSCs) Connect hepatic inflammation with Hepatocellular [7] signaling both (in vitro) and tumor LCSC expansion carcinoma xenografts (in vivo) IL-6/STAT3 cells (in vitro) Suppress cancer growth Colorectal cancer [48] signaling and metastasis

tumorigenesis and metastasis [44]. Another feedback loop, IL-6 and lncRNA CUDR cooperation aggravates lnc-BM/JAK2 and IL-6/STAT3 signaling was also report- hepatocyte-like stem cells malignant transformation ed to mediate recruitment of macrophages enhancing through NF-κB signaling, and in turn, phosphorylated breast cancer brain metastases (BCBM) [45]. NF-κB promotes the expression and phosphorylation of Some lncRNA could also behave like a tumor inhib- STAT3. This molecule binds to the promoter region of itor through IL-6/STAT3 signaling pathway. Tumor sup- miRNAs and lncRNAs to increase telomerase activity pressive lncRNA on 8p12 (TSLNC8) is fre- which leads to the malignant transformation of quently deleted and downregulated in HCC tissues but is a hepatocyte-like stem cells [47]. Through its mediation of tumor suppressor that inactivates the IL-6/STAT3 signaling cross-talk between TNF-α/NF-κβ signaling and IL-6/ pathway [46]. LncRNA prostate cancer associated tran- STAT3 cascade, DILC was reported to be an important script 29 (PCAT29) suppressed cell viability via IL-6/ tumor suppressor and is thought to be a potentially critical STAT3/miR-21 pathway [47]. determinant in both the inflammatory microenvironment IL-6 has been previously shown to exhibit enhanced and CSC expansion [7, 48]. The most relevant lncRNAs activity in cancer stem cells (CSCs) and cooperation with involved in pathological processes dysregulating IL-6 sig- lncRNAs to trigger the malignant transformation of CSCs. naling pathway are summarized in Table 1. 1144 Zhang, and Chu

FUTURE DIRECTIONS should maximize the efficiency and minimize side effects of drugs with the help of local delivery by making efforts to The effect of lncRNA on IL-6 activity is still under fully evaluate innovative personalized treatment. investigation. However, the promise of such molecules as biological markers remains clear. For example, lncRNAs FUNDING may be able to predict whether a patient will develop a disease in which IL-6 signaling dysregulation is vitally This work is supported by the Fundamental Research involved. Thus, lncRNAs will further help to determine Funds for Provincial Universities to Maolin Chu. This the use of IL-6 targeting strategies. However, for the spe- work is also supported by Hei Long Jiang Postdoctoral cific purpose of determining drug types for IL-6 targeting Foundation (LBH-Z18226) to Juan Zhang. to be administered, i.e., monoclonal antibodies or small molecules for IL-6 signaling, specific lncRNAs can pro- COMPLIANCE WITH ETHICAL STANDARDS vide efficient and specific directions on which might achieve better efficiency in the context of serious diseases Conflicts of Interest. The authors have no conflict of or complications. The lncRNAs may even help to deter- interest to declare. mine the treatment program, therapy duration of length, or become treatment biomarker responses to minimize the Publisher’sNoteSpringer Nature remains neutral with adverse effects. Furthermore, some lncRNAs, such as regard to jurisdictional claims in published maps and insti- lncRNA-SRLR, which behaves by evoking IL-6/STAT3 tutional affiliations. axis, may serve as a predictive biomarker for inherent drug resistance, and therefore as a therapeutic target to enhance responses to a specific kind of drug [49]. REFERENCES Increasing evidence has shown that lncRNAs which mediate IL-6 dysregulated diseases have great therapeutic potential, providing advantages over traditional IL-6- 1. Rosenbaum, L. 2017. Tragedy, perseverance, and chance - the story targeting agents. For instance, development of neutralizing of CAR-T therapy. The New England Journal of Medicine 377: 1313–1315. antibodies against the IL-6-targeting-antibody-proteins 2. Ishihara, K., and T. Hirano. 2002. IL-6 in autoimmune disease and leads to a loss of responsiveness after initially successful chronic inflammatory proliferative disease. Cytokine & Growth treatment. Additionally, small molecules are also less likely Factor Reviews 13: 357–368. to disrupt protein-protein or protein-DNA interacting sur- 3. Bharti, R., G. Dey, and M. Mandal. 2016. Cancer development, chemoresistance, epithelial to mesenchymal transition and stem cells: faces. One vital advantage of lncRNA-mediated control is a snapshot of IL-6 mediated involvement. Cancer Letters 375: 51–61. the ability to tightly control gene expression via mecha- 4. Yao, X., J. Huang, H. Zhong, N. Shen, R. Faggioni, M. Fung, and Y. nisms such as protein- or DNA-binding. In addition, the Yao. 2014. Targeting interleukin-6 in inflammatory autoimmune – regulatory relationship between components of IL-6 sig- diseases and cancers. Pharmacology & Therapeutics 141: 125 139. 5. Smolen, J.S., M.M. Schoels, N. Nishimoto, F.C. Breedveld, G.R. naling pathway and lncRNAs seems to be reciprocal. The Burmester, M. Dougados, P. Emery, G. Ferraccioli, C. Gabay, A. key point here lies in the determination of lncRNAs that Gibofsky, J.J. Gomez-Reino, G. Jones, T.K. Kvien, M. Murakami, play the pivotal role in the vicious circle, and challenges N. Betteridge, C.O. Bingham III, V. Bykerk, E.H. Choy, B. Combe, M. Cutolo, W. Graninger, A. Lanas, E. Martin-Mola, C. Montecucco, still remain before the clinical use of lncRNA-targeting M. Ostergaard, K. Pavelka, A. Rubbert-Roth, N. Sattar, M. Scholte- therapeutics is possible. Voshaar, Y. Tanaka, M. Trauner, G. Valentini, K.L. Winthrop, M. de Finally, several drugs have been reported to exert Wit, and D. van der Heijde. 2013. Consensus statement on blocking beneficial effects at least partly through regulation of ex- the effects of interleukin-6 and in particular by interleukin-6 receptor inhibition in rheumatoid arthritis and other inflammatory conditions. pression for some lncRNAs related to IL-6 signaling. For Annals of the Rheumatic Diseases 72: 482–492. example, emodin may attenuate cell apoptosis and inflam- 6. Huarte, M. 2015. The emerging role of lncRNAs in cancer. Nature mation as it was demonstrated to release IL-6 induced by Medicine 21: 1253–1261. LPS by inhibiting the NF-κBpathwaysvia upregulation of 7. Wang, X., W. Sun, W. Shen, M. Xia, C. Chen, D. Xiang, B. Ning, X. Cui, H. Li, X. Li, J. Ding, and H. Wang. 2016. Long non-coding TUG1 in murine chondrogenic ATDC5 cells [50]. Under- RNA DILC regulates liver cancer stem cells via IL-6/STAT3 axis. standing the pharmacological interactions between drugs Journal of Hepatology 64: 1283–1294. and lncRNAs will be of great help for appropriate drug- 8. Garbers, C., S. Heink, T. Korn, and S. Rose-John. 2018. Interleukin- design. Besides, the interactions between drugs and 6: designing specific therapeutics for a complex cytokine. Nature Reviews. Drug Discovery 17: 395–412. lncRNAs are closely related to cell and tissue type. We Targeting of IL-6-relevant Long Noncoding RNA Profiles 1145

9. Wolf, J., S. Rose-John, and C. Garbers. 2014. Interleukin-6 and its 25. Bai, Y.H., Y. Lv, W.Q. Wang, et al. 2018. LncRNA NEAT1 pro- receptors: a highly regulated and dynamic system. Cytokine 70: 11–20. motes inflammatory response and induces corneal neovasculariza- 10. Ji,P.,S.Diederichs,W.Wang,S.Boing,R.Metzger,C.Muller- tion. Journal of Molecular Endocrinology 61: 231–239. Tidow, et al. 2003. MALAT-1, a novel noncoding RNA, and thy- 26. Zhang, F., L. Wu, J. Qian, B. Qu, S. Xia, T. La, Y. Wu, J. Ma, J. mosin beta4 predict metastasis and survival in early-stage non-small Zeng, Q. Guo, Y. Cui, W. Yang, J. Huang, W. Zhu, Y. Yao, N. Shen, cell lung cancer. Oncogene 22: 8031–8041. and Y. Tang. 2016. Identification of the long noncoding RNA 11. Zhuang, Y.T., D.Y. Xu, G.Y. Wang, et al. 2017. IL-6 induced NEAT1 as a novel inflammatory regulator acting through MAPK lncRNA MALAT1 enhances TNF-alpha expression in LPS- pathway in human lupus. Journal of Autoimmunity 75: 96–104. induced septic cardiomyocytes via activation of SAA3. European 27. Wang, Q., W. Wang, F. Zhang, Y.Deng, and Z. Long. 2017. NEAT1/ Review for Medical and Pharmacological Sciences 21: 302–309. miR-181c regulates osteopontin (OPN)-mediated synoviocyte pro- 12. Chen, H., X. Wang, X. Yan, X. Cheng, X. He, and W. Zheng. 2018. liferation in osteoarthritis. Journal of Cellular Biochemistry 118: LncRNA MALAT1 regulates sepsis-induced cardiac inflammation 3775–3784. and dysfunction via interaction with miR-125b and p38 MAPK/Nf 28. Obaid, M., S.M.N. Udden, P. Deb, N. Shihabeddin, M.H. Zaki, and kappaB. International Immunopharmacology 55: 69–76. S.S. Mandal. 2018. LncRNA HOTAIR regulates 13. Wang, L.Q., and H.J. Zhou. 2018. LncRNA MALAT1 promotes lipopolysaccharide-induced cytokine expression and inflammatory high glucose-induced inflammatory response of microglial cells via response in macrophages. Scientific Reports 8: 15670. provoking MyD88/IRAK1/TRAF6 signaling. Scientific Reports 8: 29. Liu, J., G.Q. Huang, and Z.P. Ke. 2018. Silence of long intergenic 8346. noncoding RNA HOTAIR ameliorates oxidative stress and inflam- 14. Puthanveetil, P., S. Chen, B. Feng, A. Gautam, and S. Chakrabarti. mation response in ox-LDL-treated human macrophages by upreg- 2015. Long non-coding RNA MALAT1 regulates hyperglycaemia ulating miR-330-5p. Journal of Cellular Physiology 6. induced inflammatory process in the endothelial cells. Journal of 30. Huang,W.,X.Lan,X.Li,D.Wang,Y.Sun,Q.Wang,H.Gao,and Cellular and Molecular Medicine 19: 1418–1425. K. Yu. 2017. Long non-coding RNA PVT1 promote LPS-induced 15. Wang, Y., W. Nie, K. Yao, et al. 2016. induces expres- septic acute kidney injury by regulating TNFalpha and JNK/NF- sion of NADPH oxidase 2 in human aortic endothelial cells via long kappaB pathways in HK-2 cells. International noncoding RNA MALAT1. Pharmazie 71: 592–597. Immunopharmacology 47: 134–140. 16. Dai, L., G. Zhang, Z. Cheng, X. Wang, L. Jia, X. Jing, H. Wang, R. 31. Wen, Y., Y. Yu, and X. Fu. 2017. LncRNA Gm4419 contributes to Zhang, M. Liu, T. Jiang, Y. Yang, and M. Yang. 2018. Knockdown OGD/R injury of cerebral microglial cells via IkappaB phosphory- of LncRNA MALAT1 contributes to the suppression of inflamma- lation and NF-kappaB activation. Biochemical and Biophysical tory responses by up-regulating miR-146a in LPS-induced acute Research Communications 487: 923–929. lung injury. Connective Tissue Research 59: 581–592. 32. Li, X., Y.Dai, S. Yan, Y.Shi, B. Han, J. Li, L. Cha, and J. Mu. 2017. 17. Li,H.,H.Shi,N.Ma,P.Zi,Q.Liu,andR.Sun.2018.BML-111 Down-regulation of lncRNA KCNQ1OT1 protects against myocar- alleviates acute lung injury through regulating the expression of dial ischemia/reperfusion injury following acute myocardial infarc- lncRNA MALAT1. Archives of Biochemistry and Biophysics 649: tion. Biochemical and Biophysical Research Communications 491: 15–21. 1026–1033. 18. Li, S., Y. Sun, L. Zhong, Z. Xiao, M. Yang, M. Chen, C. Wang, X. 33. Hofmann, P., J. Sommer, K. Theodorou, et al. 2018. Long non- Xie, and X. Chen. 2018. The suppression of ox-LDL-induced in- coding RNA H19 regulates endothelial cell aging via inhibition of flammatory cytokine release and apoptosis of HCAECs by long Stat3 signaling. Cardiovascular Research:13. non-coding RNA-MALAT1 via regulating microRNA-155/SOCS1 34. Jin,H.,X.J.Du,Y.Zhao,andD.L.Xia.2018.XIST/miR-544axis pathway. Nutrition, Metabolism, and Cardiovascular Diseases 28: induces neuropathic pain by activating STAT3 in a rat model. 1175–1187. Journal of Cellular Physiology 233: 5847–5855. 19. Pan, L., D. Liu, L. Zhao, L. Wang, M. Xin, and X. Li. 2018. Long 35. Yuan,M.,S.Wang,L.Yu,B.Qu,L.Xu,L.Liu,H.Sun,C.Li,Y. noncoding RNA MALAT1 alleviates lipopolysaccharide-induced Shi, and H. Liu. 2017. Long noncoding RNA profiling revealed inflammatory injury by upregulating microRNA-19b in murine differentially expressed lncRNAs associated with disease activity in chondrogenic ATDC5 cells. Journal of Cellular Biochemistry 119: PBMCs from patients with rheumatoid arthritis. PLoS One 12: 10165–10175. e0186795. 20. Zhao, G., Z. Su, D. Song, Y. Mao, and X. Mao. 2016. The long 36. Wang,Z.,X.Chi,L.Liu,Y.Wang,X.Mei,Y.Yang,andT.Jia. noncoding RNA MALAT1 regulates the lipopolysaccharide- 2018. Long noncoding RNA maternally expressed gene 3 knock- induced inflammatory response through its interaction with NF- down alleviates lipopolysaccharide-induced inflammatory injury by kappaB. FEBS Letters 590: 2884–2895. up-regulation of miR-203 in ATDC5 cells. Biomedicine & Pharma- 21. Zhang,X.,X.Tang,K.Liu,M.H.Hamblin,andK.J.Yin.2017. cotherapy 100: 240–249. Long noncoding RNA Malat1 regulates cerebrovascular pathologies 37. Li, F., J. Sun, S. Huang, G. Su, and G. Pi. 2018. LncRNA GAS5 in ischemic stroke. The Journal of Neuroscience 37: 1797–1806. overexpression reverses LPS-induced inflammatory injury and apo- 22. Huang, Q., C. Huang, Y. Luo, F. He, and R. Zhang. 2018. Circulat- ptosis through up-regulating KLF2 expression in ATDC5 ing lncRNA NEAT1 correlates with increased risk, elevated severity chondrocytes. Cellular Physiology and Biochemistry 45: 1241– and unfavorable prognosis in sepsis patients. The American Journal 1251. of Emergency Medicine 36: 1659–1663. 38. Sun, T., J. Yu, L. Han, S. Tian, B. Xu, X. Gong, Q. Zhao, and Y. 23. Xia, L.X., C. Ke, and J.M. Lu. 2018. NEAT1 contributes to neuro- Wang. 2018. Knockdown of long non-coding RNA RP11-445H22.4 pathic pain development through targeting miR-381/HMGB1 axis alleviates LPS-induced injuries by regulation of MiR-301a in oste- in CCI rat models. Journal of Cellular Physiology 233: 7103–7111. oarthritis. Cellular Physiology and Biochemistry 45: 832–843. 24. Chen, D.D., L.L. Hui, X.C. Zhang, and Q. Chang. 2018. NEAT1 39. Ye, J., C. Wang, D. Wang, and H. Yuan. 2018. LncRBA GSA5, up- contributes to ox-LDL-induced inflammation and oxidative stress in regulated by ox-LDL, aggravates inflammatory response and MMP macrophages through inhibiting miR-128. Journal of Cellular Bio- expression in THP-1 macrophages by acting like a sponge for miR- .chemistry 11 221. Experimental Cell Research 369: 348–355. 1146 Zhang, and Chu

40. Binder, S., N. Hosler, D. Riedel, et al. 2017. STAT3-induced long 46. Zhang, J., Z. Li, L. Liu, Q. Wang, S. Li, D. Chen, Z. Hu, T. Yu, J. noncoding RNAs in multiple myeloma cells display different prop- Ding, J. Li, M. Yao, S. Huang, Y. Zhao, and X. He. 2018. Long erties in cancer. Scientific Reports 7: 7976. noncoding RNA TSLNC8 is a tumor suppressor that inactivates the 41. Sun, Y., J. Pan, N. Zhang, W. Wei, S. Yu, and L. Ai. 2017. Knock- interleukin-6/STAT3 signaling pathway. Hepatology 67: 171–187. down of long non-coding RNA H19 inhibits multiple myeloma cell 47. Zheng, Q., Z. Lin, X. Li, X. Xin, M. Wu, J. An, X. Gui, T. Li, H. Li, growth via NF-kappaB pathway. Scientific Reports 7: 18079. and D. Lu. 2016. Inflammatory cytokine IL6 cooperates with CUDR 42. Wang,W.T.,H.Ye,P.P.Wei,B.W.Han,B.He,Z.H.Chen,andY.Q. to aggravate hepatocyte-like stem cells malignant transformation Chen. 2016. LncRNAs H19 and HULC, activated by oxidative stress, through NF-kappaB signaling. Scientific Reports 6: 36843. promote cell migration and invasion in cholangiocarcinoma through a 48. Gu, L.Q., X.L. Xing, H. Cai, A.F. Si, X.R. Hu, Q.Y. Ma, M.L. ceRNA manner. Journal of Hematology & Oncology 9: 117. Zheng, R.Y. Wang, H.Y. Li, and X.P. Zhang. 2018. Long non-coding 43. Kong, Y.G., M. Cui, S.M. Chen, Y. Xu, Y. Xu, and Z.Z. Tao. 2018. RNA DILC suppresses cell proliferation and metastasis in colorectal LncRNA-LINC00460 facilitates nasopharyngeal carcinoma tumor- cancer. Gene 666: 18–26. igenesis through sponging miR-149-5p to up-regulate IL6. Gene 49. Xu, Z., F. Yang, D. Wei, B. Liu, C. Chen, Y. Bao, Z. Wu, D. Wu, H. 639: 77–84. Tan, J. Li, J. Wang, J. Liu, S. Sun, L. Qu, and L. Wang. 2017. Long 44. Su, K., Q. Zhao, A. Bian, et al. 2018. A novel positive feedback noncoding RNA-SRLR elicits intrinsic sorafenib resistance via regulation between long noncoding RNA UICC and IL-6/STAT3 evoking IL-6/STAT3 axis in renal cell carcinoma. Oncogene 36: signaling promotes cervical cancer progression. American Journal 1965–1977. of Cancer Research 8: 1176–1189. 50. Liang, Z., and C. Ren. 2018. Emodin attenuates apoptosis and 45. Wang, S., K. Liang, Q. Hu, P. Li, J. Song, Y. Yang, J. Yao, L.S. inflammation induced by LPS through up-regulating lncRNA Mangala, C. Li, W. Yang, P.K. Park, D.H. Hawke, J. Zhou, Y. Zhou, TUG1 in murine chondrogenic ATDC5 cells. Biomedicine & Phar- W. Xia, M.C. Hung, J.R. Marks, G.E. Gallick, G. Lopez-Berestein, macotherapy 103: 897–902. E.R. Flores, A.K. Sood, S. Huang, D. Yu,L. Yang, and C. Lin. 2017. JAK2-binding long noncoding RNA promotes breast cancer brain metastasis. The Journal of Clinical Investigation 127: 4498–4515.